Bis-quaternary salts and processes for their preparation



Patented Jan. 26, 1954 UNITED STATES PATENT OFFICE BIS-QUATERNARY SALTS AND PROCESSES FOR THEIR PREPARATION Ronald Slack, Dennis David Libman, and David Lord Pain, Dagenham, England, assignors to May & Baker Limited, Dagenham, England, a

British company No Drawing. Application November 30, 1951, Serial No. 259,317

Claims priority, application Great Britain December 15, 1950 7 Claims.

where Z represents either an oxygen atom or a single bond and R represents either a methyl or an ethyl group and n represents either 5 or 6.

The properties of the alkylene-bis-N-(N-alkylpyrrolidinium) salts of the present invention render these compounds of especial interest as sympathetic ganglionic blocking agents. The individual pyrrolidinium compounds of outstanding interest are:

Hexamethylene-bis N (N methylpyrrolidinium) salts e. g. the dibromide.

Pentamethylene-bis N (N methylpyrrolidinium) salts e. g. the di-iodide.

The corresponding morpholinium compounds have the specific advantage of relatively low toxicity. The individual morpholinium compounds of outstanding interest are:

I-lexamethylene-bis N (N methylmorpholinium) salts e. g. the di-iodide.

Pentamethylene-bis-N (N methylmorpholinium) salts e. g. the di-iodide.

It will be appreciated that the nature of the anion of the salts of the present invention is not critical from the therapeutic standpoint; obviously anions which are pharmacologically undesirable should be avoided. Examples of suitable salts are the bromide, chloride, iodide, bitartrate, citrate and neutral sulphate.

The compounds of the present invention may be prepared by the application of any of the general methods heretofore known for the production of bis-quaternary ammonium salts all of which, when so applied, can be regarded 2 as residing in the interaction of a compound of the type:

X-(CI-Iz)n-X and a compound Y, such that X represents an N-pyrrolidino or N-morpholino group or the acid residue of a reactive ester and when X represents the pyrrolidino or morpholino group Y represents a reactive ethyl or methyl ester and when X.

represents the acid residue of a reactive ester e. g. a halogen atom Y represents an N-methyl (or -ethyl) -pyrrolidine or -morpholine followed by, if the anion of the salt formed is not that required in the final product, conversion of the salt so formed into the required salt e. g. by-

metathesis or through the hydroxide.

In the case of those quaternary ammonium salts of which the anion corresponds to the acid radical of a reactive ester (such, for example, as the halides and p-toluene sulphonates) it is preferred, in practice, to adopt either of 1 the following processes:

(a) Forming the corresponding polymethylene bis-pyrrolidines or -morpholines as by condensing a reactive polymethylene di-ester, e. g. dihalide, with pyrrolidine or morpholine, isolating the same and treating the isolated base with a reactive ethyl or methyl ester, such as ethyl or methyl chloride, bromide, iodide or sulphate;

(b) Condensing a corresponding reactive po1y-' methylene di-ester, e. g. dihalide, with an N- methyl (or -ethyl) -pyrrolidine or -morpholine.

As already indicated, salts not directly obtainable by either of the two aforesaid processes e. g. the sulphates, tartrates, citrates and phosphates can be formed from the salts so obtainable either by direct metathesis or through the hydroxide. A particularly convenient method for producing water-soluble salts of this type containing the hexamethylene radical (and which can also be applied asa method for isolating water-soluble hexamethylene salts produced by direct quaternation) consists in treating an aqueous solution containing the required cation (and obtained by means of one of the aforesaid processes) with a water-solublesalt of 2:2 dihydroxy 1:1 dinaphthylmethane 3:3- dicarboxylic acid (which acid-also called embonic acid-is practically insoluble in water even 1.0 g. of lzfi-dimorpholinohexane in cos. of alcohol is treated with 5.0 g. of methyl iodide and the mixture warmed gently for a short :time. The resulting product is recrystallisedirom methanol to give hexamethylene bis-N-(N-methylmorphclinium) di-iodide, M. P. 212- C.

Example II 1.0 g. of 1:6-dimorpholinohexane is dissolved in 5 cos. of ethyl iodide and the solution refluxed on the steam bath for 1 hours. The resulting solid is recrystallised from methanol to give hexamethylene bis-N (N ethylmorpholinium) di-iodide, M. P. 249 C. (decomp).

The 1:6-dimorpholinohexane used in Examples I and II is obtained in the following manner:

24 g. of lzfiedibromo-n-hexane is added to .a solution of 102 g. of morpholine in dry benzene and the mixture is heated under reflux for 1.6 hours. After pouring into .dilute hydrochloric acid, the aqueous liquors .are separated, shaken with benzene (the benzene extracts being dis,- carded) and made alkaline with strong caustic soda solution. The crude product is extracted with ether, washed with water and the solution dried and evaporated. Distillation of the residue gives pure 1zfi-dimorpholino-n-hexane, B. P. 190 C./11 mm., M. P. 41 C.

Example III 2.5 g. of N-methylpyrrolidine in i0 cc. of absolute alcohol is heated at 100 C. for 4 hours with 2.6 g. of lzfi-dibromohexane. The solid wh ch separates on cooling is filtered and recrystallised from n-butanol to give hexamethylene-bis- N-(N-methylpyrrolidiniurn) dibromide, M. P. 227-230 C.

Example IV and extracted with hot dry ethyl alcohol. Hexamethylene-l :S-bis-N- (N methgylpyrrolidinium) (ii-iodide crystallises from the extract on cooling.

Recrystallised from alcohol, it has M. P. 178- Example VI 260 g. of 1:4-dibromobutane are added dropwise during 1 hour to a refluxing mixture of to g. of lzfi-diaminohexane, 150 g. of potassium car-- bonate and 600 cc. of alcohol. The mixture is refluxed for a further 6 hours. The alcohol is The resulting solid H a sealed tube at 100 C. for 16 hours.

4 evaporated, water is added and the mixture is thoroughly extracted with ether. The ethereal extracts are dried over magnesium sulphate; the ether is evaporated and the residue is distilled in vacuo giving 1 :G-bis-N- (N-pyrrolidino) -hexane, B. Pt. 1'76-190 C./40 mm.

30%. of .the 1:e-bis(N pyrrolidinoy-hexane in 200 ml. acetone are added -,dl'-QpWi with icecooling and shaking to a solution of 50 ml. of methyl iodide in 400 ml. of acetone. After the exothermic reaction has moderated, the mixture is heated on the steam bath for a few minutes. A-f-ter cooling, hexarnethylene-l :6 bis N- (N- methylpyrrolidinium) di-iodide, which precipitates, is filtered off and recrystallised from alcohol. M. P. 17347 9? C.

Example VII 10.1 g. of N-methylmorpholine and 2.5 g. of 1:5- dibromopentane in 10 ml. of alcohol are heated a sealed tube at 100 C. for 16 hours. Pentameth-ylene 1 5-bis-N- (N-methylmorpholinium) dibromide separates and is recrystallised from al- 001101, M. P. 239-44) C.

Example VIII 9 g. of N-methylmorpholine, 7.3 .g. of 1:6di

bromohexane, 9 g. of sodium iodide in 20 ml. of

acetone are heated in a sealed tube at 100 C, for 15 hours. The mixture is cooled, filtered and the solid extracted with hot dry alcohol. l-lexa methylened d-bis-N-(N methylmorpholinium) di-iodide separates from the extract on cooling is recrystallised from methanol, M. P. 216- 217" C. 7

Example IX 3.0 g. of N-ethylpyrrolidine and 2.4 g. of 1:6- dibromohexane in 10 ml. alcohol are heated in Hexamethylene-l 6-bis*l ,l (N-ethylpyrrolidinium) mide is precipitated with ether and recrystallised from sec-butanol, M. P. 287 C.

Example -X 2.5 g. of hexamethylene-l:6-bis-N-(N-methylpyrrolidiniuni) dibromide is dissolved in hot water and the solution added slowly to a, boiling solution of the sodium salt of embonio acid -(prepared from 4.62 g. of free acid). The sparingly soluble embonate thus precipitated is collected.

washed in the usual manner and recrystallised from methanol-ether to give yellow needles, M. P.

2.6 g. of the said embonate are dissolved in 200 cos. of boiling water-and a hot aqueous solution oi 0.76 g. of tartaric acid is then slowly added thereto. After slow cooling, free embonic acid precipitated is removed and the filtrate evaporated to dryness in vacuo. The residue is recrystals lised from methanol-ether to give the pure hexamethylene-l zfi-biseN- (N methyl yrrolidiniuml bitartrate, M. P. l-.-19.6 -C.

We claim:

1. Quaternary ammonium salts which contain the cation:

where R. represents a member of the class consisting of methyl and ethyl and n is at least 5 and not greater than 6.

2. Hexamethylene-bissWN-methylpyrrolidini um) salts.

3. Hexamethylene-bis-N-(N-methylpyrrolidina, straight chain alkylene group containing at ium )dibromide. least 5 and not more than 6 carbon atoms.

4. Hexamethylene-bis-N-(N-methylpyrrolidin- RONALD SLACK. ium) bitartrate. DENNIS DAVID LIBMAN.

5. Pentamethylene-bis-N-(N-methylpyrrolidin- 5 DAVID LORD PAIN. ium) salts.

6. Pentamethylene-bis-N-(N-methylpyrrolidin- References Cited in the file Of this Patent ium) bitartrate di-iodide.

7 y t y1 t y1p 1 Nledellt J. Amel. Chem. SOC. May V01.

um) salts in which the polymethylene bridge is 10 8404' 

1. QUATERNARY AMMONIUM SALTS WHICH CONTAIN THE CATION: 